Bioinformatic prospecting and synthesis of a bifunctional lipopeptide antibiotic that evades resistance

TY - JOUR

T1 - Bioinformatic prospecting and synthesis of a bifunctional lipopeptide antibiotic that evades resistance

AU - Wang, Zongqiang

AU - Koirala, Bimal

AU - Hernandez, Yozen

AU - Zimmerman, Matthew

AU - Brady, Sean F.

N1 - Publisher Copyright: © 2022 American Association for the Advancement of Science. All rights reserved.

PY - 2022/5/27

Y1 - 2022/5/27

N2 - Emerging resistance to currently used antibiotics is a global public health crisis. Because most of the biosynthetic capacity within the bacterial kingdom has remained silent in previous antibiotic discovery efforts, uncharacterized biosynthetic gene clusters found in bacterial genome-sequencing studies remain an appealing source of antibiotics with distinctive modes of action. Here, we report the discovery of a naturally inspired lipopeptide antibiotic called cilagicin, which we chemically synthesized on the basis of a detailed bioinformatic analysis of the cil biosynthetic gene cluster. Cilagicin's ability to sequester two distinct, indispensable undecaprenyl phosphates used in cell wall biosynthesis, together with the absence of detectable resistance in laboratory tests and among multidrug-resistant clinical isolates, makes it an appealing candidate for combating antibiotic-resistant pathogens.

AB - Emerging resistance to currently used antibiotics is a global public health crisis. Because most of the biosynthetic capacity within the bacterial kingdom has remained silent in previous antibiotic discovery efforts, uncharacterized biosynthetic gene clusters found in bacterial genome-sequencing studies remain an appealing source of antibiotics with distinctive modes of action. Here, we report the discovery of a naturally inspired lipopeptide antibiotic called cilagicin, which we chemically synthesized on the basis of a detailed bioinformatic analysis of the cil biosynthetic gene cluster. Cilagicin's ability to sequester two distinct, indispensable undecaprenyl phosphates used in cell wall biosynthesis, together with the absence of detectable resistance in laboratory tests and among multidrug-resistant clinical isolates, makes it an appealing candidate for combating antibiotic-resistant pathogens.

UR - https://www.scopus.com/pages/publications/85130871963

U2 - 10.1126/science.abn4213

DO - 10.1126/science.abn4213

M3 - Article

C2 - 35617397

SN - 0036-8075

VL - 376

JO - Science

JF - Science

IS - 6596

M1 - eabn4213

ER -